Leveraging infectious disease models to interpret randomized controlled trials: Controlling enteric pathogen transmission through water, sanitation, and hygiene interventions.

Randomized controlled trials (RCTs) evaluate hypotheses in specific contexts and are often considered the gold standard of evidence for infectious disease interventions, but their results cannot immediately generalize to other contexts (e.g., different populations, interventions, or disease burdens). Mechanistic models are one approach to generalizing findings between contexts, but infectious disease transmission models (IDTMs) are not immediately suited for analyzing RCTs, since they often rely on time-series surveillance data. We developed an IDTM framework to explain relative risk outcomes of an infectious disease RCT and applied it to a water, sanitation, and hygiene (WASH) RCT. This model can generalize the RCT results to other contexts and conditions. We developed this compartmental IDTM framework to account for key WASH RCT factors: i) transmission across multiple environmental pathways, ii) multiple interventions applied individually and in combination, iii) adherence to interventions or preexisting conditions, and iv) the impact of individuals not enrolled in the study. We employed a hybrid sampling and estimation framework to obtain posterior estimates of mechanistic parameter sets consistent with empirical outcomes. We illustrated our model using WASH Benefits Bangladesh RCT data (n = 17,187). Our model reproduced reported diarrheal prevalence in this RCT. The baseline estimate of the basic reproduction number [Formula: see text] for the control arm (1.10, 95% CrI: 1.07, 1.16) corresponded to an endemic prevalence of 9.5% (95% CrI: 7.4, 13.7%) in the absence of interventions or preexisting WASH conditions. No single pathway was likely able to sustain transmission: pathway-specific [Formula: see text] for water, fomites, and all other pathways were 0.42 (95% CrI: 0.03, 0.97), 0.20 (95% CrI: 0.02, 0.59), and 0.48 (95% CrI: 0.02, 0.94), respectively. An IDTM approach to evaluating RCTs can complement RCT analysis by providing a rigorous framework for generating data-driven hypotheses that explain trial findings, particularly unexpected null results, opening up existing data to deeper epidemiological understanding.

Fine-scale spatial clustering of measles nonvaccination that increases outbreak potential is obscured by aggregated reporting data.

The United States experienced historically high numbers of measles cases in 2019, despite achieving national measles vaccination rates above the World Health Organization recommendation of 95% coverage with two doses. Since the COVID-19 pandemic began, resulting in suspension of many clinical preventive services, pediatric vaccination rates in the United States have fallen precipitously, dramatically increasing risk of measles resurgence. Previous research has shown that measles outbreaks in high-coverage contexts are driven by spatial clustering of nonvaccination, which decreases local immunity below the herd immunity threshold. However, little is known about how to best conduct surveillance and target interventions to detect and address these high-risk areas, and most vaccination data are reported at the state-level-a resolution too coarse to detect community-level clustering of nonvaccination characteristic of recent outbreaks. In this paper, we perform a series of computational experiments to assess the impact of clustered nonvaccination on outbreak potential and magnitude of bias in predicting disease risk posed by measuring vaccination rates at coarse spatial scales. We find that, when nonvaccination is locally clustered, reporting aggregate data at the state- or county-level can result in substantial underestimates of outbreak risk. The COVID-19 pandemic has shone a bright light on the weaknesses in US infectious disease surveillance and a broader gap in our understanding of how to best use detailed spatial data to interrupt and control infectious disease transmission. Our research clearly outlines that finer-scale vaccination data should be collected to prevent a return to endemic measles transmission in the United States.

Identifying optimal vaccination scenarios to reduce varicella zoster virus transmission and reactivation.

BACKGROUND: Varicella zoster virus (VZV) is one of the eight known human herpesviruses. Initial VZV infection results in chickenpox, while viral reactivation following a period of latency manifests as shingles. Separate vaccines exist to protect against both initial infection and subsequent reactivation. Controversy regarding chickenpox vaccination is contentious with most countries not including the vaccine in their childhood immunization schedule due to the hypothesized negative impact on immune-boosting, where VZV reactivation is suppressed through exogenous boosting of VZV antibodies from exposure to natural chickenpox infections. METHODS: Population-level chickenpox and shingles notifications from Thailand, a country that does not vaccinate against either disease, were previously fitted with mathematical models to estimate rates of VZV transmission and reactivation. Here, multiple chickenpox and shingles vaccination scenarios were simulated and compared to a model lacking any vaccination to analyze the long-term impacts of VZV vaccination. RESULTS: As expected, simulations suggested that an introduction of the chickenpox vaccine, at any coverage level, would reduce chickenpox incidence. However, chickenpox vaccine coverage levels above 35% would increase shingles incidence under realistic estimates of shingles coverage with the current length of protective immunity from the vaccine. A trade-off between chickenpox and shingles vaccination coverage was discovered, where mid-level chickenpox coverage levels were identified as the optimal target to minimize total zoster burden. Only in scenarios where shingles vaccine provided lifelong immunity or coverage exceeded current levels could large reductions in both chickenpox and shingles be achieved. CONCLUSIONS: The complicated nature of VZV makes it impossible to select a single vaccination scenario as universal policy. Strategies focused on reducing both chickenpox and shingles incidence, but prioritizing the latter should maximize efforts towards shingles vaccination, while slowly incorporating chickenpox vaccination. Alternatively, countries may wish to minimize VZV complications of both chickenpox and shingles, which would lead to maximizing vaccine coverage levels across both diseases. Balancing the consequences of vaccination to overall health impacts, including understanding the impact of an altered mean age of infection for both chickenpox and shingles, would need to be considered prior to any vaccine introduction.

The variant-specific burden of SARS-CoV-2 in Michigan: March 2020 through November 2021.

Accurate estimates of the total burden of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are needed to inform policy, planning, and response. We sought to quantify SARS-CoV-2 cases, hospitalizations, and deaths by age in Michigan. Coronavirus disease 2019 cases reported to the Michigan Disease Surveillance System were multiplied by age and time-specific adjustment factors to correct for under-detection. Adjustment factors were estimated in a model fit to incidence data and seroprevalence estimates. Age-specific incidence of SARS-CoV-2 hospitalization, death, vaccination, and variant proportions were estimated from publicly available data. We estimated substantial under-detection of infection that varied by age and time. Accounting for under-detection, we estimate the cumulative incidence of infection in Michigan reached 75% by mid-November 2021, and over 87% of Michigan residents were estimated to have had ≥1 vaccination dose and/or previous infection. Comparing pandemic waves, the relative burden among children increased over time. In general, the proportion of cases who were hospitalized or who died decreased over time. Our results highlight the ongoing risk of periods of high SARS-CoV-2 incidence despite widespread prior infection and vaccination. This underscores the need for long-term planning for surveillance, vaccination, and other mitigation measures amidst continued response to the acute pandemic.

Understanding the mechanisms of HPV-related carcinogenesis: Implications for cell cycle dynamics.

The role of human papillomavirus (HPV) as a causative agent for epithelial cancers is well-known, but many open questions remain regarding the downstream gene regulatory effects of viral proteins E6 and E7 on the cell cycle. Here, we extend a cell cycle model originally presented by Gérard and Goldbeter (2009) in order to capture the effects of E6 and E7 on key actors in the cell cycle. Results suggest that E6 is sufficient to reverse p53-induced quiescence, while E7 is sufficient to reverse p16INK4a-induced quiescence; both E6 and E7 are necessary when p53 and p16INK4a are both active. Moreover, E7 appears to play a role as a "growth factor substitute", inducing cell division in the absence of growth factor. Low levels of E7 may permit regular cell division, but the results suggest that higher levels of E7 dysregulate the cell cycle in ways that may destabilize the cellular genome. The mechanisms explored here provide opportunities for developing new treatment targets that take advantage of the cell cycle regulatory system to prevent HPV-related cancer effects.

Protective impacts of household-based tuberculosis contact tracing are robust across endemic incidence levels and community contact patterns.

There is an emerging consensus that achieving global tuberculosis control targets will require more proactive case finding approaches than are currently used in high-incidence settings. Household contact tracing (HHCT), for which households of newly diagnosed cases are actively screened for additional infected individuals is a potentially efficient approach to finding new cases of tuberculosis, however randomized trials assessing the population-level effects of such interventions in settings with sustained community transmission have shown mixed results. One potential explanation for this is that household transmission is responsible for a variable proportion of population-level tuberculosis burden between settings. For example, transmission is more likely to occur in households in settings with a lower tuberculosis burden and where individuals mix preferentially in local areas, compared with settings with higher disease burden and more dispersed mixing. To better understand the relationship between endemic incidence levels, social mixing, and the impact of HHCT, we developed a spatially explicit model of coupled household and community transmission. We found that the impact of HHCT was robust across settings of varied incidence and community contact patterns. In contrast, we found that the effects of community contact tracing interventions were sensitive to community contact patterns. Our results suggest that the protective benefits of HHCT are robust and the benefits of this intervention are likely to be maintained across epidemiological settings.

Stigmatizing Policies Interact with Mental Health and Sexual Behaviours to Structurally Induce HIV Diagnoses Among European Men Who Have Sex with Men.

Structural stigma shapes men who have sex with men's (MSM's) mental health and sexual behaviours. The aim of this study was to examine how stigmatizing policies interact with downstream anxiety/depression and sexual behaviours to structurally pattern HIV disparities among European MSM. We conducted a secondary data analysis of the European Men-who-have-sex-with-men Internet Survey (EMIS) from 2017. We included a total of 98,600 participants living in 39 European countries. We used the Rainbow Index, a score given to countries based on their sexual and gender minority policies as the predictor of HIV diagnosis. We conducted adjusted random intercept and slope multi-level logistic regressions. In adjusted models, higher Rainbow Index scores was associated with lower predictive probabilities of diagnosed HIV, regardless of the number of condomless intercourse partners. The predictive probability of HIV diagnosis was also lower, regardless of severity of anxiety/depression, where the Rainbow Index score was better. Country-level policies interact with downstream sexual behaviours and anxiety/depression to structurally influence HIV diagnosis among MSM in Europe.

Severe Acute Respiratory Syndrome Coronavirus 2 Surveillance in Decedents in a Large, Urban Medical Examiner's Office.

BACKGROUND: Given the challenges in implementing widespread testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is increasing interest in alternative surveillance strategies. METHODS: We tested nasopharyngeal swabs from 1094 decedents in the Wayne County Medical Examiner's Office for SARS-CoV-2. All decedents were assessed using a coronavirus disease 2019 (COVID-19) checklist, and decedents flagged using the checklist (298) were preferentially tested. A random sample of decedents not flagged using the checklist were also tested (796). We statistically analyzed the characteristics of decedents (age, sex, race, and manner of death), differentiating between those flagged using the checklist and not and between those SARS-CoV-2-positive and not. RESULTS: A larger percentage of decedents overall were male (70% vs 48%) and black (55% vs 36%) compared with the catchment population. Seven-day average percent positivity among flagged decedents closely matched the trajectory of percent positivity in the catchment population, particularly during the peak of the outbreak (March and April 2020). After a lull in May to mid-June, new positive tests in late June coincided with increased case detection in the catchment. We found large racial disparities in test results; SARS-CoV-2-positive decedents were substantially more likely to be black than SARS-CoV-2-negative decedents (82% vs 51%). SARS-CoV-2-positive decedents were also more likely to be older and to have died of natural causes, including of COVID-19 disease. CONCLUSIONS: Disease surveillance through medical examiners and coroners could supplement other forms of surveillance and serve as a possible early outbreak warning sign.

Exploring the Seasonal Drivers of Varicella Zoster Virus Transmission and Reactivation.

Varicella zoster virus (VZV) is a herpesvirus that causes chickenpox and shingles. The biological mechanisms underpinning the multidecadal latency of VZV in the body and subsequent viral reactivation-which occurs in approximately 30% of individuals-are largely unknown. Because chickenpox and shingles are endemic worldwide, understanding the relationship between VZV transmission and reactivation is important for informing disease treatment and control. While chickenpox is a vaccine-preventable childhood disease with a rich legacy of research, shingles is not a notifiable disease in most countries. To date, population-level studies of shingles have had to rely on small-scale hospital or community-level data sets. Here, we examined chickenpox and shingles notifications from Thailand and found strong seasonal incidence in both diseases, with a 3-month lag between peak chickenpox transmission season and peak shingles reactivation. We tested and fitted 14 mathematical models examining the biological drivers of chickenpox and shingles over an 8-year period to estimate rates of VZV transmission, reactivation, and immunity-boosting, wherein reexposure to VZV boosts VZV-specific immunity to reinforce protection against shingles. The models suggested that the seasonal cycles of chickenpox and shingles have different underlying mechanisms, with ambient levels of ultraviolet radiation being correlated with shingles reactivation.

Immunologic and Epidemiologic Drivers of Norovirus Transmission in Daycare and School Outbreaks.

BACKGROUND: Norovirus outbreaks are notoriously explosive, with dramatic symptomology and rapid disease spread. Children are particularly vulnerable to infection and drive norovirus transmission due to their high contact rates with each other and the environment. Despite the explosive nature of norovirus outbreaks, attack rates in schools and daycares remain low with the majority of students not reporting symptoms. METHODS: We explore immunologic and epidemiologic mechanisms that may underlie epidemic norovirus transmission dynamics using a disease transmission model. Towards this end, we compared different model scenarios, including innate resistance and acquired immunity (collectively denoted 'immunity'), stochastic extinction, and an individual exclusion intervention. We calibrated our model to daycare and school outbreaks from national surveillance data. RESULTS: Including immunity in the model led to attack rates that were consistent with the data. However, immunity alone resulted in the majority of outbreak durations being relatively short. The addition of individual exclusion (to the immunity model) extended outbreak durations by reducing the amount of time that symptomatic people contribute to transmission. Including both immunity and individual exclusion mechanisms resulted in simulations where both attack rates and outbreak durations were consistent with surveillance data. CONCLUSIONS: The epidemiology of norovirus outbreaks in daycare and school settings cannot be well described by a simple transmission model in which all individuals start as fully susceptible. More studies on how best to design interventions which leverage population immunity and encourage more rigorous individual exclusion may improve venue-level control measures. See video abstract at http://links.lww.com/EDE/B795.

Epidemiology of the silent polio outbreak in Rahat, Israel, based on modeling of environmental surveillance data.

Israel experienced an outbreak of wild poliovirus type 1 (WPV1) in 2013-2014, detected through environmental surveillance of the sewage system. No cases of acute flaccid paralysis were reported, and the epidemic subsided after a bivalent oral polio vaccination (bOPV) campaign. As we approach global eradication, polio will increasingly be detected only through environmental surveillance. We developed a framework to convert quantitative polymerase chain reaction (qPCR) cycle threshold data into scaled WPV1 and OPV1 concentrations for inference within a deterministic, compartmental infectious disease transmission model. We used this approach to estimate the epidemic curve and transmission dynamics, as well as assess alternate vaccination scenarios. Our analysis estimates the outbreak peaked in late June, much earlier than previous estimates derived from analysis of stool samples, although the exact epidemic trajectory remains uncertain. We estimate the basic reproduction number was 1.62 (95% CI 1.04-2.02). Model estimates indicate that 59% (95% CI 9-77%) of susceptible individuals (primarily children under 10 years old) were infected with WPV1 over a little more than six months, mostly before the vaccination campaign onset, and that the vaccination campaign averted 10% (95% CI 1-24%) of WPV1 infections. As we approach global polio eradication, environmental monitoring with qPCR can be used as a highly sensitive method to enhance disease surveillance. Our analytic approach brings public health relevance to environmental data that, if systematically collected, can guide eradication efforts.

Time-varying survival effects for squamous cell carcinomas at oropharyngeal and nonoropharyngeal head and neck sites in the United States, 1973-2015.

BACKGROUND: Anatomical site is strongly associated with head and neck cancer etiology, and etiology and patient sociodemographic characteristics are prognostic factors for survival. It is not known whether the effects of these predictors persist over the postdiagnosis period or are strongest proximal to the time of diagnosis. METHODS: Using survival times and causes of death for 180,434 patients with head and neck cancer in the Surveillance, Epidemiology, and End Results cancer registry (1973-2015), the empirical cumulative incidences of cancer-specific death and other-cause death were calculated with a competing risks framework, and the time-dependent effects (hazard ratios) of anatomical tumor site (oropharynx, oral cavity, or hypopharynx/larynx), age, sex, race, and year of diagnosis on cancer-specific death and other-cause death, stratified by tumor stage, were estimated. RESULTS: All effects were significantly time-varying (P < .001). Patients with nonoropharyngeal cancer had a higher hazard of cancer-specific death but a similar cumulative fraction of deaths because of a higher rate of death from other causes. Cancer-specific survival has not changed for patients with nonoropharyngeal cancer over the past decades but has improved since 2000 for patients with oropharyngeal cancer. The effects of age and sex on cancer survival were strongest proximal to the diagnosis, whereas the effect of race persisted over time. CONCLUSIONS: Recent improvements in survival for patients with oropharyngeal cancer may be due more to an increasing fraction of cancers attributable to human papillomavirus than to increasing treatment effectiveness. The prognostic strength of anatomical site and other predictors changes over the postdiagnosis period. LAY SUMMARY: It is generally assumed that the effects of tumor and personal characteristics on the survival of patients with head and neck cancer are fixed over time, but this study shows that many factors are most important only in the first few years after diagnosis. Also, recent improvements in the survival of patients with head and neck cancer appear to benefit only patients with cancers of the oropharynx. The improvements may be due more to an increasing fraction of cancers caused by human papillomavirus (which generally have better outcomes) than to advances in head and neck cancer treatment overall.

The Impact of Vaccination Efforts on the Spatiotemporal Patterns of the Hepatitis A Outbreak in Michigan, 2016-2018.

BACKGROUND: The United States is currently experiencing the largest hepatitis A virus (HAV) outbreak since the introduction of a vaccine in 1996. More than 31,000 cases have been reported since 2016. Although HAV had largely been considered a foodborne pathogen in recent years, this outbreak has been spread primarily through person-to-person transmission in urban settings and has been associated with homelessness and substance use. Michigan was one of the first states to report an outbreak, with 910 reported cases between August 2016 and December 2018. METHODS: We analyzed surveillance and vaccination data from Michigan using a disease transmission model to investigate how vaccine timing and coverage influenced the spatiotemporal patterns of the outbreak, distinguishing between Southeast Michigan, where the outbreak began, and the rest of the state. RESULTS: We estimated that vaccination had little impact in Southeast Michigan (3% cases averted [95% confidence interval (CI) = 1%, 8%]) but had a substantial impact in the rest of the state, preventing a larger outbreak (91% cases averted [95% CI = 85%, 97%]) lasting several more years. CONCLUSIONS: Our results emphasize the value of targeting populations where local transmission is not yet sustained rather than populations where transmission is already waning. Simulation modeling can aid in proactive rather than reactive decision-making and may help direct the response to outbreaks emerging in other states. See video abstract: http://links.lww.com/EDE/B704.

Identification of the Fraction of Indolent Tumors and Associated Overdiagnosis in Breast Cancer Screening Trials.

It is generally accepted that some screen-detected breast cancers are overdiagnosed and would not progress to symptomatic cancer if left untreated. However, precise estimates of the fraction of nonprogressive cancers remain elusive. In recognition of the weaknesses of overdiagnosis estimation methods based on excess incidence, there is a need for model-based approaches that accommodate nonprogressive lesions. Here, we present an in-depth analysis of a generalized model of breast cancer natural history that allows for a mixture of progressive and indolent lesions. We provide a formal proof of global structural identifiability of the model and use simulation to identify conditions that allow for parameter estimates that are sufficiently precise and practically actionable. We show that clinical follow-up after the last screening can play a critical role in ensuring adequately precise identification of the fraction of indolent cancers in a stop-screen trial design, and we demonstrate that model misspecification can lead to substantially biased estimates of mean sojourn time. Finally, we illustrate our findings using the example of Canadian National Breast Screening Study 2 (1980-1985) and show that the fraction of indolent cancers is not precisely identifiable. Our findings provide the foundation for extended models that account for both in situ and invasive lesions.

Multisite HPV infections in the United States (NHANES 2003-2014): An overview and synthesis.

HPV is the most common sexually transmitted infection in the U.S., infecting both anogenital and oral sites. Nationally representative data are collected through the National Health and Nutrition Examination Survey (NHANES). However, changing designations of HPV genotypes as high or low risk and varying underlying populations as new results are reported have made direct comparison of results difficult. We reanalyzed HPV data from NHANES derived from self-collected cervicovaginal swabs (women ages 18-59, 2003-14), penile swabs (men ages 18-59, 2013-14), and oral rinses (men and women ages 18-69, 2009-14), using consistent populations and definitions across NHANES cycles. These data strengthen our understanding of age trends in HPV prevalence: cervicovaginal prevalence decreases with age, penile prevalence increases with age, and oral prevalence is bimodal but with an earlier first peak in women. There is strong evidence for reduced prevalence of vaccine genotypes (6, 11, 16, 18) in vaccinated men and women (ages 18-24) at both genital (RR 0.2 (0.1-0.3) in women and 0.7 (0.1-5.4) in men) and oral sites (RR 0.1 (0.0-1.3) in women; no infections detected in vaccinated men). A more complete picture of the burden of HPV in the U.S. is emerging, including evidence for reduced HPV genital and oral prevalence in vaccinated individuals.

Comparing alternative cholera vaccination strategies in Maela refugee camp: using a transmission model in public health practice.

BACKGROUND: Cholera is a major public health concern in displaced-person camps, which often contend with overcrowding and scarcity of resources. Maela, the largest and longest-standing refugee camp in Thailand, located along the Thai-Burmese border, experienced four cholera outbreaks between 2005 and 2010. In 2013, a cholera vaccine campaign was implemented in the camp. To assist in the evaluation of the campaign and planning for subsequent campaigns, we developed a mathematical model of cholera in Maela. METHODS: We formulated a Susceptible-Infectious-Water-Recovered-based transmission model and estimated parameters using incidence data from 2010. We next evaluated the reduction in cases conferred by several immunization strategies, varying timing, effectiveness, and resources (i.e., vaccine availability). After the vaccine campaign, we generated case forecasts for the next year, to inform on-the-ground decision-making regarding whether a booster campaign was needed. RESULTS: We found that preexposure vaccination can substantially reduce the risk of cholera even when <50% of the population is given the full two-dose series. Additionally, the preferred number of doses per person should be considered in the context of one vs. two dose effectiveness and vaccine availability. For reactive vaccination, a trade-off between timing and effectiveness was revealed, indicating that it may be beneficial to give one dose to more people rather than two doses to fewer people, given that a two-dose schedule would incur a delay in administration of the second dose. Forecasting using realistic coverage levels predicted that there was no need for a booster campaign in 2014 (consistent with our predictions, there was not a cholera epidemic in 2014). CONCLUSIONS: Our analyses suggest that vaccination in conjunction with ongoing water sanitation and hygiene efforts provides an effective strategy for controlling cholera outbreaks in refugee camps. Effective preexposure vaccination depends on timing and effectiveness. If a camp is facing an outbreak, delayed distribution of vaccines can substantially alter the effectiveness of reactive vaccination, suggesting that quick distribution of vaccines may be more important than ensuring every individual receives both vaccine doses. Overall, this analysis illustrates how mathematical models can be applied in public health practice, to assist in evaluating alternative intervention strategies and inform decision-making.

Phenotypic variations in persistence and infectivity between and within environmentally transmitted pathogen populations impact population-level epidemic dynamics.

BACKGROUND: Human pathogens transmitted through environmental pathways are subject to stress and pressures outside of the host. These pressures may cause pathogen pathovars to diverge in their environmental persistence and their infectivity on an evolutionary time-scale. On a shorter time-scale, a single-genotype pathogen population may display wide variation in persistence times and exhibit biphasic decay. METHODS: We use a transmission modeling framework to develop an infectious disease model with biphasic pathogen decay. We take a differential algebra approach to assessing model identifiability, calculate basic reproduction numbers by the next generation method, and use simulation to explore model dynamics. RESULTS: For both long and short time-scales, we demonstrate that epidemic-potential-preserving trade-offs have implications for epidemic dynamics: less infectious, more persistent pathogens cause epidemics to progress more slowly than more infectious, less persistent (labile) pathogens, even when the overall risk is the same. Using identifiability analysis, we show that the usual disease surveillance data does not sufficiently inform these underlying pathogen population dynamics, even when combined with basic environmental monitoring data. However, risk could be indirectly ascertained by developing methods to separately monitor labile and persistent subpopulations. Alternatively, determining the relative infectivity of persistent pathogen subpopulations and the rates of phenotypic conversion will help ascertain how much disease risk is associated with the long tails of biphasic decay. CONCLUSION: A better understanding of persistence-infectivity trade-offs and associated dynamics can improve our ecological understanding of environmentally transmitted pathogens, as well as our risk assessment and disease control strategies.

HPV vaccination has not increased sexual activity or accelerated sexual debut in a college-aged cohort of men and women.

BACKGROUND: The human papillomavirus (HPV) is the most common sexually transmitted infection and is linked to several types of cancer. HPV vaccination uptake in the U.S. is relatively low, despite the vaccine's high efficacy. Some parents of adolescents have concerns that vaccination will encourage sexual behavior and therefore choose not to vaccinate. Previous studies investigating vaccination and sexual behavior have included only young women and girls. METHODS: The objective of this study is to assess associations between HPV-vaccination and sexual behavior in a college-age cohort of both men and women. We analyzed questionnaire data collected from the Michigan HPV and Oropharyngeal Cancer Study, a cohort study designed to investigate HPV infection and its association with sexual behavior (data collected 2015-17, Ann Arbor, MI). Here, we consider vaccination status, sexual behavior, and substance use among 241 college-aged men and women. Logistic, Poisson, and Cox regression were used to determine the relationship between probability of sexual debut, number of sexual partners, and HPV vaccination status at baseline as well as between age at sexual debut and vaccination status at debut. RESULTS: HPV vaccination status was not significantly associated with an increased likelihood of sexual debut (odds ratio: 0.80 (95% CI: 0.41-1.58), decreased age of sexual debut (hazard ratio: 0.81 (95% CI: 0.65-1.00), nor an increased number of sexual partners (per year sexually active; incidence rate ratio: 1.27 (95% CI: 0.86-1.87)) in this cohort, after controlling for age, race, sex, and substance use. Instead, race or alcohol use were independent predictors of sexual behavior. CONCLUSIONS: Concerns about the influence of the HPV vaccine on sexual behavior are likely unfounded for both men and women. These results can aid in increasing vaccine acceptability, inform and strengthen physician recommendations, and ultimately reduce the burden of HPV and HPV-related cancers in the U.S.

Linking Decision Theory and Quantitative Microbial Risk Assessment: Tradeoffs Between Compliance and Efficacy for Waterborne Disease Interventions.

Achieving health gains from the U.N. Sustainable Development Goals of universal coverage for water and sanitation will require interventions that can be widely adopted and maintained. Effectiveness-how an intervention performs based on actual use-as opposed to efficacy will therefore be central to evaluations of new and existing interventions. Incomplete compliance-when people do not always use the intervention and are therefore exposed to contamination-is thought to be responsible for the lower-than-expected risk reductions observed from water, sanitation, and hygiene interventions based on their efficacy at removing pathogens. We explicitly incorporated decision theory into a quantitative microbial risk assessment model. Specifically, we assume that the usability of household water treatment (HWT) devices (filters and chlorine) decreases as they become more efficacious due to issues such as taste or flow rates. Simulations were run to examine the tradeoff between device efficacy and usability. For most situations, HWT interventions that trade lower efficacy (i.e., remove less pathogens) for higher compliance (i.e., better usability) contribute substantial reductions in diarrheal disease risk compared to devices meeting current World Health Organization efficacy guidelines. Recommendations that take into account both the behavioral and microbiological properties of treatment devices are likely to be more effective at reducing the burden of diarrheal disease than current standards that only consider efficacy.

Correction: Parameter estimation for multistage clonal expansion models from cancer incidence data: A practical identifiability analysis.

[This corrects the article DOI: 10.1371/journal.pcbi.1005431.].